“[The use of] …vasopressin infusion for treatment of vasodilatory shock after cardiac surgery may improve some clinically important outcomes.”

Image: S. Shernan, Brigham and Women’s Hospital.

Image: S. Shernan, Brigham and Women’s Hospital.

HAJJAR et al.1  designed, conducted, and now report in this issue an elegant randomized double-blind controlled trial of vasopressin (0.01 to 0.06 U/min) versus norepinephrine (10 to 60 μg/min) post cardiac surgery with vasodilatory shock (Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock After Cardiac Surgery [VANCS] trial). Open-label norepinephrine was added if there was an inadequate response to blinded study drug. Vasodilatory shock was defined by hypotension requiring vasopressors and a cardiac index greater than 2.2 l · min · m-2. The primary endpoint was a composite: “mortality or severe complications.” Patents with vasodilatory shock within 48 h post cardiopulmonary bypass weaning were eligible. Three hundred patients were included, and there was a highly significant decrease in the primary endpoint in the vasopressin compared to the norepinephrine group (absolute risk reduction 17%, number needed to treat 6). There was also a significantly lower rate of atrial fibrillation in the vasopressin versus norepinephrine group (perhaps expected because of lack of β1-adrenergic stimulation with vasopressin). The vasopressin group also had sparing of norepinephrine (shorter duration), shorter duration of study drug infusion, shorter intensive care unit stay, shorter duration of dobutamine, less acute kidney injury, less need for renal replacement therapy, and lower sepsis-related organ failure assessment scores than the norepinephrine group. The authors conclude that vasopressin is superior to norepinephrine in vasodilatory shock after cardiac surgery. There was no difference in 28-day mortality in the composite—the vasopressin signal was driven by severe complications and not by mortality in the mortality or severe complications composite.

Strengths of VANCS include the blinded randomized treatment, careful follow-up, calculation of the composite outcome, achieving adequate and planned sample size, and evaluation of vasopressin pharmacokinetics.

Nearly 20 yr ago, Landry et al.2–6  discovered relative vasopressin deficiency and benefits of prophylactic (i.e., pre cardiopulmonary bypass) and postoperative low-dose vasopressin infusion in patients with vasodilatory shock after cardiac surgery. Previous trials of vasopressin versus norepinephrine in cardiac surgery were small and underpowered for mortality assessment.2–6 

Vasopressin stimulates arginine vasopressin receptor 1a, arginine vasopressin receptor 1b, V2, oxytocin, and purinergic receptors causing vasoconstriction (V1a), corticosteroid axis stimulation (V1b), and antidiuresis (V2), as well as release of procoagulant von Willebrand multimers (V2). Mechanisms of vasopressin benefit in VANCS include sparing of norepinephrine7  or other nonhemodynamic effects (because hemodynamics such as mean arterial pressure, cardiac index, lactate, and fluid balance were similar in vasopressin and norepinephrine groups). Trials of vasopressin versus norepinephrine in septic shock show no difference between vasopressin and norepinephrine in efficacy or adverse effects,8–11  contrasting with the possible efficacy and the atrial fibrillation avoidance benefit of vasopressin in the randomized controlled trial by Hajjar et al.1  Dunser et al.12  found fewer tachyarrhythmias with vasopressin compared with norepinephrine in vasodilatory shock. Why was vasopressin possibly beneficial in vasodilatory syndrome after cardiac surgery in VANCS1  but not in septic shock in the Vasopressin and Septic Shock trial (VASST; registered with http://www.controlled-trials.com, ISRCTN94845869; supported by grant no. MCT 44152 from the Canadian Institutes of Health Research, Ottawa, Canada) or VAsopressin versus Noradrenaline as Initial therapy in Septic shock trial (VANISH)?8,11  The most obvious difference is the primary outcome—mortality and severe complications in VANCS, 28-day mortality in VASST,8  and kidney failurefree days in VANISH.11  Although vasopressin doses in VASST, VANISH,11  and VANCS1  were similar, peak vasopressin levels on vasopressin treatment were much lower in the VANCS (20 to 25 pmol/l) than in the VASST (80 to 100 pmol/l) or the VANISH pilot trial10,11  (300 pmol/l). Perhaps lower vasopressin levels in VANCS are the optimal vasopressin level in vasodilatory shock due to septic shock or post cardiac surgery. This aligns with the observation that the vasopressin beneficial signal in VANCS was restricted to lower rates of adverse effects of vasopressin.

Aspects of variability of patient response to vasopressin infusion and other purported mechanisms of action of vasopressin (and V1a agonism) deserve emphasis. Interindividual responses to vasopressin may be due to polymorphisms of leucyl/cystinyl aminopeptidase, the enzyme that catalyzes vasopressin13  or the V1a receptor. Recently, V1a agonism14–16  was found to decrease vascular leak in models and possibly in patients with septic shock,17  perhaps by limiting increases in angiopoietin-2,16,18  and may be another reason for vasopressin’s efficacy in the trial by Hajjar et al.1 

Hajjar et al.1  note that vasodilatory shock after cardiac surgery is common in patients previously treated with β-blockers or angiotensin-converting enzyme inhibitors. In their trial, 65% of patients were on β-blockers and 46% of the norepinephrine group and 35% of the vasopressin group were on angiotensin-converting enzyme inhibitors. The vasopressin benefit occurred in patients with or without β-blockers, but only in the patients on angiotensin-converting enzyme inhibitors. These are hypothesis-generating post hoc subgroup analyses to be interpreted with caution. Perhaps Hajjar et al.1  discovered a novel interaction of vasopressin with angiotensin-converting enzyme pathways, a possible scenario from a biological standpoint.

The mortality rates were high—16 and 15% at 28 days and 17 and 16% at 90 days (norepinephrine vs. vasopressin)—in VANCS1 ; remarkably, mortality rates were not reported in previous smaller trials of vasopressin versus norepinephrine for vasodilatory shock12  after cardiac surgery.2,5,6,19 

There are limitations of the current trial, including that it is a single-center trial. The major limitation is that the primary endpoint was changed after the trial had enrolled some patients, an important protocol amendment. How many patients had been included by then? Was a change in protocol registered? How did this alter the sample size and power calculations? The sample size and power calculation of the initial endpoint (days alive and free of organ dysfunction [Brussels score]) should be stated. The authors explain well the rationale and process for changing the primary endpoint in the electronic supplement. Interestingly, the vasopressin group had significantly more days alive and free of cardiovascular and renal dysfunction compared to the norepinephrine group.

There is concern about generalizability of these results in other countries and healthcare settings. The lengths of intensive care unit stay (6 days) and hospital stay (10 to 13 days) appear prolonged because patients with vasodilatory shock have more profound derangements after cardiac surgery that extend intensive care unit and hospital stays. The literature is sparse regarding expected lengths of stay after vasodilatory shock complicating cardiac surgery, which is the reason that Hajjar et al.1  changed the primary outcome. It would also be useful to understand how the lengths of stay of vasodilatory shock patients compared to those of patients in the hospital of Hajjar et al.1  in Brazil who did not have vasodilatory shock post cardiac surgery.

In summary, this remarkable trial shows that in settings such as the study hospital, vasopressin infusion for treatment of vasodilatory shock after cardiac surgery may improve some clinically important outcomes. Pocock and Stone20  emphasize limitations of “positive” trials, including having the primary P value merely less than 0.05 as being inadequate to change practice (they suggest P < 0.001; P was 0.0014 in VANCS), magnitude of the treatment benefit (absolute risk reduction was 16%—impressive—in VANCS), having an important primary outcome (mortality and severe complications are clinically important), careful inspection of composite outcomes (vasopressin decreased severe complications), having supportive secondary outcomes (atrial fibrillation was lower with vasopressin), consistency across subgroups (some consistency; e.g., β-blockers yes/no subgroups), stopping early (not the case in VANCS), flaws in trial design or conduct (the change in primary endpoint in VANCS as discussed), and applicability to a reader’s patients, an issue I addressed. Accordingly, this trial deserves replication in other multicenter healthcare settings to create confidence about generalizability. A selective V1a agonist may be more effective than vasopressin by limiting von Willebrand factor release and vascular leak, rationales for future randomized controlled trials of V1a agonism in vasodilatory shock after cardiac surgery.

Research Support

Supported by grant No. MCT 44152 from the Canadian Institutes of Health Research, Ottawa, Canada.

Competing Interests

Dr. Russell reports patents owned by the University of British Columbia (UBC), Vancouver, Canada, that are related to PCSK9 inhibitor(s) and sepsis and the use of vasopressin in septic shock. He is an inventor on these patents. He is a founder, director, and shareholder in Cyon Therapeutics Inc., Vancouver, Canada (developing a sepsis therapy). He has share options in Leading Biosciences Inc., San Diego, California. He is a shareholder in Molecular You Corp., Vancouver, Canada. He reports receiving consulting fees from Merck, Kenilworth, New Jersey (developing antibiotics), Leading Biosciences (developing a sepsis therapeutic), Ferring Pharmaceuticals, Copenhagen, Denmark (manufactures vasopressin and is developing selepressin), Grifols, Barcelona, Spain (sells albumin), La Jolla Pharmaceuticals, La Jolla, California (developing angiotensin II; he chairs the DSMB of a trial of angiotensin II), CytoVale Inc., San Francisco, California (developing a sepsis diagnostic), Asahi Kesai Pharmaceuticals of America, Waltham, Massachusetts (AKPA; developing recombinant thrombomodulin). He reports having received an investigator-initiated grant from Grifols that is provided to and administered by UBC.

References

1.
Hajjar
LA
,
Vincent
JL
,
Galas
FRBG
,
Rhodes
A
,
Landoni
G
,
Osawa
EA
,
Melo
RR
,
Sundin
MR
,
Grande
SM
,
Gaiotto
FA
,
Pomerantzeff
PM
,
Dallan
LO
,
Franco
RA
,
Nakamura
RE
,
Lisboa
LA
,
de Almeida
JP
,
Gerent
AM
,
Souza
DH
,
Gaiane
MA
,
Fukushima
JT
,
Park
CL
,
Zambolim
c
,
Ferreira
GSR
,
Strabelli
TM
,
Fernandes
FL
,
Camara
L
,
Zeferino
S
,
Santos
VG
,
Piccioni
MA
,
Jatene
FB
,
Auler
JOC
,
Filho
RK
:
Vasopressin versus norepinephrine in patients with vasoplegic shock after cardiac surgery: The VANCS randomized controlled trial.
Anesthesiology
2017
;
126
:
85
93
2.
Argenziano
M
,
Chen
JM
,
Choudhri
AF
,
Cullinane
S
,
Garfein
E
,
Weinberg
AD
,
Smith
CR
Jr
,
Rose
EA
,
Landry
DW
,
Oz
MC
:
Management of vasodilatory shock after cardiac surgery: Identification of predisposing factors and use of a novel pressor agent.
J Thorac Cardiovasc Surg
1998
;
116
:
973
80
3.
Argenziano
M
,
Chen
JM
,
Cullinane
S
,
Choudhri
AF
,
Rose
EA
,
Smith
CR
,
Edwards
NM
,
Landry
DW
,
Oz
MC
:
Arginine vasopressin in the management of vasodilatory hypotension after cardiac transplantation.
J Heart Lung Transplant
1999
;
18
:
814
7
4.
Rosenzweig
EB
,
Starc
TJ
,
Chen
JM
,
Cullinane
S
,
Timchak
DM
,
Gersony
WM
,
Landry
DW
,
Galantowicz
ME
:
Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery.
Circulation
1999
;
100
(
19 Suppl
):
II182
6
5.
Morales
DL
,
Gregg
D
,
Helman
DN
,
Williams
MR
,
Naka
Y
,
Landry
DW
,
Oz
MC
:
Arginine vasopressin in the treatment of 50 patients with postcardiotomy vasodilatory shock.
Ann Thorac Surg
2000
;
69
:
102
6
6.
Morales
DL
,
Garrido
MJ
,
Madigan
JD
,
Helman
DN
,
Faber
J
,
Williams
MR
,
Landry
DW
,
Oz
MC
:
A double-blind randomized trial: Prophylactic vasopressin reduces hypotension after cardiopulmonary bypass.
Ann Thorac Surg
2003
;
75
:
926
30
7.
Asfar
P
,
Russell
JA
,
Tuckermann
J
,
Radermacher
P
:
Selepressin in septic shock: A step toward decatecholaminization?
Crit Care Med
2016
;
44
:
234
6
8.
Russell
JA
,
Walley
KR
,
Singer
J
,
Gordon
AC
,
Hébert
PC
,
Cooper
DJ
,
Holmes
CL
,
Mehta
S
,
Granton
JT
,
Storms
MM
,
Cook
DJ
,
Presneill
JJ
,
Ayers
D
;
VASST Investigators
:
Vasopressin versus norepinephrine infusion in patients with septic shock.
N Engl J Med
2008
;
358
:
877
87
9.
Anantasit
N
,
Boyd
JH
,
Walley
KR
,
Russell
JA
:
Serious adverse events associated with vasopressin and norepinephrine infusion in septic shock.
Crit Care Med
2014
;
42
:
1812
20
10.
Gordon
AC
,
Mason
AJ
,
Perkins
GD
,
Stotz
M
,
Terblanche
M
,
Ashby
D
,
Brett
SJ
:
The interaction of vasopressin and corticosteroids in septic shock: A pilot randomized controlled trial.
Crit Care Med
2014
;
42
:
1325
33
11.
Gordon
AC
,
Mason
AJ
,
Thirunavukkarasu
N
,
Perkins
GD
,
Cecconi
M
,
Cepkova
M
,
Pogson
DG
,
Aya
HD
,
Anjum
A
,
Frazier
GJ
,
Santhakumaran
S
,
Ashby
D
,
Brett
SJ
;
VANISH Investigators
:
Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: The VANISH randomized clinical trial.
JAMA
2016
;
316
:
509
18
12.
Dünser
MW
,
Mayr
AJ
,
Ulmer
H
,
Knotzer
H
,
Sumann
G
,
Pajk
W
,
Friesenecker
B
,
Hasibeder
WR
:
Arginine vasopressin in advanced vasodilatory shock: A prospective, randomized, controlled study.
Circulation
2003
;
107
:
2313
9
13.
Nakada
TA
,
Russell
JA
,
Wellman
H
,
Boyd
JH
,
Nakada
E
,
Thain
KR
,
Thair
SA
,
Hirasawa
H
,
Oda
S
,
Walley
KR
:
Leucyl/cystinyl aminopeptidase gene variants in septic shock.
Chest
2011
;
139
:
1042
9
14.
He
X
,
Su
F
,
Taccone
FS
,
Laporte
R
,
Kjølbye
AL
,
Zhang
J
,
Xie
K
,
Moussa
MD
,
Reinheimer
TM
,
Vincent
JL
:
A selective V(1A) receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock.
Crit Care Med
2016
;
44
:
23
31
15.
Maybauer
MO
,
Maybauer
DM
,
Enkhbaatar
P
,
Laporte
R
,
Wiśniewska
H
,
Traber
LD
,
Lin
C
,
Fan
J
,
Hawkins
HK
,
Cox
RA
,
Wiśniewski
K
,
Schteingart
CD
,
Landry
DW
,
Rivière
PJ
,
Traber
DL
:
The selective vasopressin type 1a receptor agonist selepressin (FE 202158) blocks vascular leak in ovine severe sepsis.
Crit Care Med
2014
;
42
:
e525
33
16.
Rehberg
S
,
Yamamoto
Y
,
Sousse
L
,
Bartha
E
,
Jonkam
C
,
Hasselbach
AK
,
Traber
LD
,
Cox
RA
,
Westphal
M
,
Enkhbaatar
P
,
Traber
DL
:
Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis.
Am J Physiol Heart Circ Physiol
2012
;
303
:
H1245
54
17.
Russell
J, Vincent JL
,
Kjolbye
AL
,
Olsson
H
,
Blemings
A
,
Grundemar
L
:
62: Selepressin, a novel selective V1a agonist, reduces norepinephrine requirements and shortens duration of organ dysfunction in septic shock patients.
Crit Care Med
2012
;
40
:
1
328
18.
Fisher
J
,
Douglas
JJ
,
Linder
A
,
Boyd
JH
,
Walley
KR
,
Russell
JA
:
Elevated plasma angiopoietin-2 levels are associated with fluid overload, organ dysfunction, and mortality in human septic shock.
Crit Care Med
2016
;
44
:
2018
27
19.
Elgebaly
AS
,
Sabry
M
:
Infusion of low-dose vasopressin improves left ventricular function during separation from cardiopulmonary bypass: A double-blind randomized study.
Ann Card Anaesth
2012
;
15
:
128
33
20.
Pocock
SJ
,
Stone
GW
:
The primary outcome is positive—is that good enough?
N Engl J Med
2016
;
375
:
971
9